Development of LRRK2 PROTAC degraders as chemical probes and potential lead compounds for the treatment of Parkinson's disease

开发 LRRK2 PROTAC 降解剂作为治疗帕金森病的化学探针和潜在先导化合物

• 批准号: EP/X025225/1
• 负责人: Alessio Ciulli
• 金额: $ 19.5万
• 依托单位: University of Dundee
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FX025225%2F1
• 关键词: Development; LRRK2; PROTAC; degraders; chemical

Parkinson's Disease (PD) is the second most common neurodegenerative disorder worldwide and no treatment is currently available to halt the onset and/or progression of PD pharmacologically. The kinase-activating G2019S mutations in Leucine-Rich Repeat Kinase 2 (LRRK2) is one of the most common genetic causes of PD and has motivated work to develop LRRK2-targeted therapies, including LRRK2 kinase inhibitors. However, current LRRK2 kinase inhibitors, albeit in clinical trials, promote LRRK2 and microtubule association, underlying potential undesirable side effects. Alternative LRRK2-targeting strategy, known as LRRK2 Proteolysis Targeting Chimera (PROTAC) is therefore proposed. LRRK2 PROTACs are heterobifunctional small molecules that consist of a ligand that binds LRRK2, conjugated to a ligand that binds an E3 ubiquitin ligase via a linker. By recruiting a E3 ubiquitin ligase in close proximity to a LRRK2 protein, LRRK2 PROTACs can induce the ubiquitination and subsequent degradation of LRRK2 through the ubiquitin-proteasome pathway. By designing and synthesizing a few sets of LRRK2 PROTAC compounds and screening them with degradation assays on multiple cell lines, we identified potent LRRK2 PROTACs that degraded LRRK2 at nanomolar range concentrations. The goal of this fellowship is to further improve the potencies of these LRRK2 PROTACs through structural modification and qualify them as chemical probes and potential lead compounds for the treatment of PD by detailed in vitro and in vivo characterization and PD-related biology studies.

帕金森病(PD)是全球第二常见的神经退行性疾病，目前还没有有效的治疗方法来阻止PD的发生和/或进展。富亮氨酸重复序列激酶2(LRRK2)的G2019S突变是帕金森病最常见的遗传原因之一，并推动了针对LRRK2靶向治疗的研究，包括LRRK2激酶抑制剂。然而，目前的LRRK2激酶抑制剂，即使在临床试验中，也会促进LRRK2和微管的联系，从而产生潜在的不良副作用。因此，提出了另一种LRRK2靶向策略，称为LRRK2蛋白水解靶向嵌合体(PROTAC)。LRRK2PROTAC是一种异质双功能的小分子，由与LRRK2结合的配体组成，该配体与通过连接物结合E3泛素连接酶的配体结合。通过在LRRK2蛋白附近招募E3泛素连接酶，LRRK2 PROTACs可以通过泛素-蛋白酶体途径诱导LRRK2的泛素化和随后的降解。通过设计和合成几组LRRK2 PROTAC化合物，并在多个细胞系上进行降解试验筛选，我们鉴定了在纳摩尔浓度范围内降解LRRK2的有效LRRK2 PROTAC。该奖学金的目标是通过结构修饰进一步提高这些LRRK2 PROTAC的效力，并通过详细的体外和体内表征以及与PD相关的生物学研究，将它们鉴定为治疗PD的化学探针和潜在的先导化合物。

项目成果

Discovery of XL01126: A Potent, Fast, Cooperative, Selective, Orally Bioavailable, and Blood-Brain Barrier Penetrant PROTAC Degrader of Leucine-Rich Repeat Kinase 2.

XL01126的发现：一种有效，快速，合作，选择性，口服生物利用，以及富含亮氨酸的重复激酶2的血脑屏障渗透剂protac Degrader。

• DOI: 10.1021/jacs.2c05499
• 发表时间: 2022-09-21
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Liu, Xingui;Kalogeropulou, Alexia F.;Domingos, Sofia;Makukhin, Nikolai;Nirujogi, Raja S.;Singh, Francois;Shpiro, Natalia;Saalfrank, Anton;Sammler, Esther;Ganley, Ian G.;Moreira, Rui;Alessi, Dario R.;Ciulli, Alessio
• 通讯作者: Ciulli, Alessio